chr19-50402053-G-A
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_002691.4(POLD1):c.518G>A(p.Ser173Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00539 in 1,614,076 control chromosomes in the GnomAD database, including 416 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S173G) has been classified as Uncertain significance.
Frequency
Consequence
NM_002691.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLD1 | NM_002691.4 | c.518G>A | p.Ser173Asn | missense_variant | 5/27 | ENST00000440232.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLD1 | ENST00000440232.7 | c.518G>A | p.Ser173Asn | missense_variant | 5/27 | 1 | NM_002691.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0291 AC: 4435AN: 152152Hom.: 210 Cov.: 32
GnomAD3 exomes AF: 0.00770 AC: 1934AN: 251044Hom.: 90 AF XY: 0.00540 AC XY: 733AN XY: 135810
GnomAD4 exome AF: 0.00291 AC: 4249AN: 1461806Hom.: 204 Cov.: 34 AF XY: 0.00245 AC XY: 1781AN XY: 727224
GnomAD4 genome AF: 0.0292 AC: 4452AN: 152270Hom.: 212 Cov.: 32 AF XY: 0.0281 AC XY: 2090AN XY: 74464
ClinVar
Submissions by phenotype
not specified Benign:6
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 04, 2016 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 06, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 13, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Colorectal cancer, susceptibility to, 10 Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Oct 25, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 20, 2015 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Carcinoma of colon Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The POLD1 p.Ser173Asn variant was identified in dbSNP (ID: rs1726803) “With Benign allele”, ClinVar (classified benign by GeneDx, Invitae, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), and in control databases in 2724 (141 homozygous) of 276964 chromosomes at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2439 (139 homozygous) of 23962 chromosomes (freq: 0.10), Other in 20 of 6462 chromosomes (freq: 0.003), Latino in 231 (2 homozygous) of 34410 chromosomes (freq: 0.007), European Non-Finnish in 31 of 126566 chromosomes (freq: 0.0002), Ashkenazi Jewish in 1 of 10142 chromosomes (freq: 0.0001), and South Asian in 2 of 30782 chromosomes (freq: 0.00007), while not observed in the East Asian and European Finnish populations. The p.Ser173 residue is conserved in in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact of Asn to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 18, 2016 | Variant summary: The POLD1 c.518G>A (p.Ser173Asn) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a benign outcome for this variant. This variant was found in 1114/120932 control chromosomes (including 57 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.1000194 (1030/10298). This frequency is about 7041 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is a common benign polymorphism found primarily in the populations of African. Taken together, this variant is classified as Benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at